Crop losses, to both abiotic factors such as climate change and biotic factors such as predation, constitute a significant threat to crop security for a rapidly expanding global population. Biotic crop damage has been effectively reduced by both biological and chemical pest controls, the latter of which have proliferated in the last century. However, due to both environmental toxicity concerns for early insecticide generations and burgeoning insecticide resistance, new small molecule classes with novel modes of action are continuously being developed. This thesis reports chemical proteomics investigations into two recent insecticides: chlorantraniliprole (CHL) of the diamide class, using affinity-based protein profiling, and the atypical insecticide pyridalyl, using activity-based protein profiling.

Insecticide resistance can develop over time by a multitude of mechanisms. Despite offering a novel mode of action which delays selection of target-site mutants, CHL has been demonstrated to gradually decline in efficacy through insects evolving their portfolio of detoxifying enzymes to more rapidly render insecticides inert – a phenomenon termed metabolic insecticide resistance. A photoaffinity probe based on CHL incorporating a diazirine tag was synthesised, which facilitated covalent capture, isolation, and characterisation of its interactome, aiming to identify key metabolic proteins contributing to this resistance mechanism in the soybean looper (Chrysodeixis includens). Proteomics data suggest the upregulation of several cuticular proteins in the CHL-resistant soybean looper compared to the wild type. Synthetic routes towards major CHL metabolites were also established to provide reference standards for complementary metabolite identification studies.

The mode of action of pyridalyl is unknown. A collection of activity-based probes based on pyridalyl were designed and synthesised, and their cytotoxicity profiles measured in Sf9 cells using real-time microscopy. This has laid the foundation for proteomics using a prime probe candidate to capture and identify the oxidative proteins implicated in its mode of action.